Various methods are known as processes for producing N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamines, which are important for use as production intermediates for medicines, etc.
For example, a method is known wherein 1-(2-thienyl)-3-chloropropan-1-one is reduced using sodium borohydride in ethanol to obtain 3-chloro-1-(2-thienyl)-1-propanol, halogen exchange is subsequently conducted in acetone using sodium iodide to obtain 3-iodo-1-(2-thienyl)-1-propanol, and then this is reacted with a monomethylamine aqueous solution in tetrahydrofuran (CHIRALITY, 12, 26-29 (2000)). However, since the raw material used in this method is 1-(2-thienyl)-3-chloropropan-1-one, which is a very unstable compound, this method is not industrially applicable.
One example of a known method for producing N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine uses the reaction between 2-acetylthiophene and dimethylamine hydrochloride in isopropanol in the presence of paraformaldehyde and hydrochloric acid to obtain (2-thienyl)(2-dimethylaminoethyl)ketone, and the (2-thienyl)(2-dimethylaminoethyl)ketone is reduced using sodium borohydride in ethanol (JP 7-188065 A). If N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is produced in the same method as described above except that a monoalkylamine hydrochloride is used instead of the dimethylamine hydrochloride, since the production intermediate, i.e., (2-thienyl)(2-monoalkylaminoethyl)ketone, is unstable, an N,N′,N″-alkyl-bis[1-[3-oxo-3-(2-thienyl)propane]]amine, which is a dimer, is produced, and therefore the yield of the N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine obtained after the reduction using sodium borohydride is low.
A method wherein an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is obtained by reducing a (Z)—N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is also known (WO 2004/016603 A1). Therefore, there is a strong demand for a method for efficiently producing an (E,Z)—N-monoalkyl-3-oxo-3-(2-thienyl)propenamine, which is a raw material for N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamines.